The trans differentiation of pancreatic acinar cells to a duct-like, pluripotent progenitor cell type (ADM, acinar-to- ductal metaplasia) is an initial step leading to the development of pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer. ADM can be initiated after activation of the epidermal growth factor receptor, acquisition of activating mutations of Kras and macrophage-secreted cytokines. However, the common signaling mechanism driving ADM downstream of these inducers are largely unknown. It is our hypothesis that activation of a PKD1 signaling is a common feature of inducers of acinar-to-ductal metaplasia, driving the formation of PanINs and the progression to pancreatic tumors. To test this we will: Determine if activation of PKD1 is a common mechanism for different inducers of ADM (Specific Aim 1); identify PKD1 downstream signaling pathways that drive ADM and the formation of duct-like pancreatic progenitor cells (Specific Aim 2); determine if expression and/or activity of PKD1 indicate progression of ADM to PanINs and PDA in vivo (Specific Aim 3); and use genetic animal models to define the role of PKD1 in development of pancreatic cancer (Specific Aim 4). Successful completion of our project will identify PKD1 as a common feature of processes that initiate the development of pancreatic cancer. It also will define the signaling events up- and downstream of PKD1 that facilitate PanIN formation and contribute to development of pancreatic cancer. Early diagnosis and early targeting are key for successful intervention of pancreatic cancer. Our results will provide the basis for both, since PKD1 is a targetable kinase and can be a molecular signaling marker for early events.